Grant: CIHR Fellowship

The coordination of activity is present across nature, from the harmonized flight of starlings to the coordinated activity of large areas of the human brain to generate ideas. Healthy pancreatic Beta-cells coordinate their function to keep the right glucose levels in our body by secreting the required amount of insulin. Defects in Beta-cell function can lead to diabetes mellitus. More than 537 million people worldwide suffer from diabetes. Recent studies indicate that islet coordination is impaired in T2D patients. Consequently, understanding the cellular mechanisms behind Beta-cell coordination might help to develop effective therapies for diabetes. Recently, we identified a subpopulation of Beta-cells termed "leader" Beta-cells which exert disproportionate control over islet Ca2+ dynamics. The leader Beta-cells are the first cells to increase intracellular Ca2+ after glucose stimulation and serve to coordinate "follower" Beta-cells in mouse and Zebrafish islets. My own work showed that photo-ablation of Zebrafish leader cells disrupted pan-islet Ca2+ signaling, identifying these as likely pacemakers. However, none of these studies fully address the critical questions: how are the calcium waves initiated and how is coordination between a leader and follower cells achieved? There is growing evidence that intracellular Ca2+ mobilization might be playing a critical role during calcium wave initiation and spread. Hence, in this project, we will determine the effects of triggering an influx of Ca2+ vs intracellular Ca2+ mobilization in islet coordination. We will combine light-driven optogenetics, genetic and pharmacological approaches to decipher how the leader Beta-cells controls the islet's calcium dynamics. The paradigm we are developing, by examining the roles of individual cells in coordinating Ca2+ dynamic in the islet, may be applicable for other tissues where cell coordination is crucial for proper function e.g. muscles, neuronal circuits and myocardium.